Nerve injuries in humans may engender a persistent pain state that typically responds poorly to conventional analgesics/interventions. A useful model of this pain state exists in the rat, in which selective ligation of the L5/L6 spinal nerves results in reliable and quantifiable tactile hyperesthesia or allodynia, of the ipsilateral hindpaw. A growing body of literature suggests that this form of anomalous pain state may be attenuated by antagonists for several ligand-and/or voltage-gated cation channels. Numerous observations support the hypothesis that alterations in these channels and their respective receptors result in spontaneous activity in chronically injured axons and dorsal root ganglia. Spontaneous afferent activity, in conjunction with transported factors, is believed to initiate the anatomical and neurochemical reorganization of the affected sensory axon, dorsal root ganglion, and spinal dorsal horn that are ultimately responsible for the persistent pain state. These complex changes, reflecting the pathoplasticity of sensory afferent and spinal cord function following peripheral nerve injury, form the background for the following long-term objectives of the proposed work: 1) Define the role of spinal and peripheral sodium channels in regulating nerve injury-evoked hyperalgesia; 2) Characterize the effect of agents active at these channels, and of axonal transport blockade, on temporal changes in regional spinal glucose metabolism, protein kinase C activity, levels of selected primary afferent-associated neuropeptides and markers of sympathetic terminal activity in spinal cored and dorsal root ganglia; and 3) Characterize the temporal changes in anatomical markers of sodium channels in spinal cord, dorsal root ganglion cells and sensory axons following peripheral nerve lesions. Experiments are specifically designed to address the time course of the impact of exposure to ion channel antagonists and axonal transport inhibition in reversing allodynia following nerve injury, and the effects of these manipulations on regional spinal glucose utilization and membrane-bound (activated) protein kinase C. Subsequent studies will examine the nature of sodium channel alterations following peripheral nerve injury and during regeneration in the spinal cored, DRG and nerve, probing with antibodies or oligonucleotides, with attention to the possible emergence of new isoforms. Fulfillment of these aims will provide substantive insights into the mechanisms whereby nerve injury alters sensory encoding, and yield data which may materially contribute toward novel therapeutic approaches to managing neuropathic pain. In addition, the plan carried out in collaboration with expert colleagues at the University of California at San Diego, will serve to expand the expertise of the PI in several important areas of neurobiology.